Betulin is a pentacyclic triterpenoid derived from the outer bark of paper birch trees (Betula paperifera). It can be present at concentrations of up to about 24% of the bark of white birch. Merck Index, twelfth edition, page 1236, 1996. Lupeol is a related compound also found in birch bark and in other plant sources. Lupeol is present at concentrations of about 1.5-3% of birch bark and at up to about 8.2% in Canavalia ensiformis, a plant widespread in the humid tropics of Asia, India, and Africa. Allobetulin is another triterpenoid found in birch bark. A typical pulp mill that processes birch produces enough bark waste to allow for the inexpensive isolation of significant quantities of these triterpenoids.
Fungi infect humans and are a major cause of human health problems. They also infect plants and cause enormous losses in agricultural productivity. One class of fungal infections of mammals are the dermatophytic infections. These are fungal infections of the hair, nails, and skin. They are caused by fungi called xe2x80x9cdermatophytes,xe2x80x9d which include species belonging to the genera Epidermophyton, Microsporum, and Trichophyton. Among the species of dermatophytes are the following: Microsporum canis, which results in scalp and skin infections, mostly in children; Microsporum gypseum, which also results in scalp and skin infections in animals and humans; Trichophyton tonsurans, the major agent causing scalp ringworm; Trichophyton rubrum, causing skin, nail, hair, and scalp infections; and Trichophyton mentagrophytes, which can occur on all parts of the body surface.
Other fungal infectious agents include the opportunists that are likely to infect immunodeficient persons. These include Cryptococcus, Candida, and Aspergillus.
Betulin and related compounds have been shown to have anti-viral activity against herpes simplex virus. Carlson et al., U.S. Pat. No. 5,750,578.
Current agents used to treat fungal infections include the polyene antibiotics, including nystatin; synthetic azoles; and griseofulvin. Fungal infections are difficult to treat because, like humans, they are eukaryotes.
Currently, there is a need for new anti-fungal and anti-yeast agents. A need particularly exists for agents that will act against a range of species, including dermatophytic fungi, yeasts, and Candida. New anti-fungal agents would be less expensive to manufacture if they were abundant natural products or easily synthesized from abundant natural products.
The present invention provides a therapeutic method of treating a mammal afflicted with a fungal or yeast infection comprising administering to the mammal an effective anti-fungal or anti-yeast amount of a triterpene of formula (I): 
wherein
R1 is hydrogen or hydroxy;
R2 is a direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C6-C10)aryl, or (C1-C6)alkyl;
R3 is hydrogen, hydroxy, (C1-C6)alkyl, Oxe2x95x90P(OH)2, Oxe2x95x90P(OH)2OP(O)(OH)xe2x80x94, (C1-C5)alkanoyl, Si(R)3 wherein each R is H, phenyl or (C1-C6)alkyl, C(O)N(R)2, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C1-C4)alkoxy](C1-C4)alkyl, or a glycoside;
R4 is hydrogen, hydroxy, (C1-C6)alkyl, Oxe2x95x90P(OH)2, Oxe2x95x90P(OH)2OP(O)(OH)xe2x80x94, (C1-C5)alkanoyl, Si(R)3 wherein each R is H, phenyl or (C1-C6)alkyl, C(O)N(R)2, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C1-C4)alkoxy](C1-C4)alkyl, or a glycoside; or R4 and R5 together are oxo; and
R5 is direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C6-C10)aryl, or (C1-C6)alkyl; or R4 and R5 together are oxo;
wherein any alkyl can optionally be substituted with one or more halo, hydroxy, (C6-C10)aryl, nitro, cyano, (C1-C6)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR7R8, wherein R7 and R8 are each independently hydrogen, (C1-C6)alkyl or polyethyleneimine; or C(xe2x95x90O)OR9, wherein R9 is hydrogen, (C1-C6)alkyl, or polyethyleneimine;
each of the bonds represented by xe2x80x94 is independently absent or is present;
wherein any alkyl is optionally interrupted on carbon with one or more oxy, thio, sulfinyl, sulfonyl, polyethyleneimine, or poly(ethylene glycol);
wherein any alkyl is optionally partially unsaturated;
wherein any aryl can optionally be substituted with one or more halo, hydroxy, nitro, cyano, (C1-C6)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR7R8, wherein R7 and R8 are each independently hydrogen, (C1-C6)alkyl or polyethyleneimine; or C(xe2x95x90O)OR9, wherein R9 is hydrogen, (C1-C6)alkyl, or polyethyleneimine;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a therapeutic method of treating a mammal afflicted with a fungal or yeast infection comprising administering to the mammal an effective anti-fungal or anti-yeast amount of a triterpene of formula (II): 
wherein
one of R1 and R2 is xe2x80x94Oxe2x80x94Y and the other is hydrogen or (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy, halo, halo(C1-C6)alkoxy or NRjRk wherein Rj and Rk are independently H, (C1-C6)alkyl or (C1-C6)alkonyl; or R1 and R2 together are oxo (xe2x95x90O);
R3 is hydrogen, halo, carboxy, mercapto, (C1-C6)alkyl, (C3-C8)cycloalkyl, or xe2x80x94Oxe2x80x94Y;
R4 and R5 are each independently hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl;
R6 is hydrogen or is absent when the adjacent xe2x80x94 is a bond;
R7 is hydrogen or (C1-C6)alkyl;
R8 is hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl and R11 is hydrogen, (C1-C6)alkyl, carboxy, or hydroxy(C1-C6)alkyl; or R8 and R11 together are xe2x80x94Oxe2x80x94C(xe2x95x90X)xe2x80x94;
R9 and R10, are each independently hydrogen or (C1-C6)alkyl;
each of the bonds represented by xe2x80x94 is independently absent or is present;
X is two hydrogens, oxo (xe2x95x90O) or thioxo (xe2x95x90S);
each Y is independently H, aryl, P(O)(Cl)2, (C3-C8)cycloalkyl, adamantyl, xe2x80x94SO2Ra Oxe2x95x90P(Rb)2, Oxe2x95x90P(Rc)2OP(O)(Rd)xe2x80x94, Si(Re)3, tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and xe2x80x94N(Rf)xe2x80x94; wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (xe2x95x90O), hydroxy, carboxy, halo, mercapto, nitro, xe2x80x94N(Rg)(Rh), (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide; and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
Ra is (C1-C6)alkyl or aryl;
Rb, Rc, and Rd are each independently hydroxy, (C1-C6)alkoxy, hydroxy(C2-C6)alkoxy, adamantyloxy, adamantyl(C1-C6)alkoxy, norbornyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C1-C6)alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C3-C8)cycloalkyloxy, NRxRy, or aryloxy;
Re is H, aryl or (C1-C6)alkyl;
Rf is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl;
Rg and Rh are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, adamantyl, adamantyl(C1-C6)alkyl, amino(C1-C6)alkyl, aminosulfonyl, (C1-C6)alkanoyl, aryl and benzyl; or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical; and
Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, aryl or benzyl;
wherein each aryl of Y, Ra-Rd, Rg-Rh, Rx, and Ry may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NRiRj, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, trifluoromethoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, or (C1-C6)alkanoyloxy; wherein Ri and Rj are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl, or benzyl;
wherein any alkyl can optionally be substituted with one or more polyethyleneimine or poly(ethylene glycol); and wherein any alkyl can optionally be interrupted with one or more polyethyleneimine or poly(ethylene glycol);
or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of inhibiting or killing a fungus or yeast, comprising contacting the fungus or yeast with an effective anti-fungal or anti-yeast amount of a triterpene of formula (I): 
wherein
R1 is hydrogen or hydroxy;
R2 is a direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C6-C10)aryl, or (C1-C6)alkyl;
R3 is hydrogen, hydroxy, (C1-C6)alkyl, Oxe2x95x90P(OH)2, Oxe2x95x90P(OH)2OP(O)(OH)xe2x80x94, (C1-C5)alkanoyl, Si(R)3 wherein each R is H, phenyl or (C1-C6)alkyl, C(O)N(R)2, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C1-C4)alkoxy](C1-C4)alkyl, or a glycoside;
R4 is hydrogen, hydroxy, (C1-C6)alkyl, Oxe2x95x90P(OH)2, Oxe2x95x90P(OH)2OP(O)(OH)xe2x80x94, (C1-C5)alkanoyl, Si(R)3 wherein each R is H, phenyl or (C1-C6)alkyl, C(O)N(R)2, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C1-C4)alkoxy](C1-C4)alkyl, or a glycoside; or R4 and R5 together are oxo; and
R5 is direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C6-C10)aryl, or (C1-C6)alkyl; or R4 and R5 together are oxo;
wherein any alkyl can optionally be substituted with one or more halo, hydroxy, (C6-C10)aryl, nitro, cyano, (C1-C6)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR7R8, wherein R7 and R8 are each independently hydrogen, (C1-C6)alkyl or polyethyleneimine; or C(xe2x95x90O)OR9, wherein R9 is hydrogen, (C1-C6)alkyl, or polyethyleneimine;
each of the bonds represented by xe2x80x94 is independently absent or is present;
wherein any alkyl is optionally interrupted on carbon with one or more oxy, thio, sulfinyl, sulfonyl, polyethyleneimine, or poly(ethylene glycol);
wherein any alkyl is optionally partially unsaturated;
wherein any aryl can optionally be substituted with one or more halo, hydroxy, nitro, cyano, (C1-C6)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR7R8, wherein R7 and R8 are each independently hydrogen, (C1-C6)alkyl or polyethyleneimine; or C(xe2x95x90O)OR9, wherein R9 is hydrogen, (C1-C6)alkyl, or polyethyleneimine;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of inhibiting or killing a fungus or yeast comprising contacting the fungus or yeast with an effective anti-fungal or anti-yeast amount of a triterpene of formula (II): 
wherein
one of R1 and R2 is xe2x80x94Oxe2x80x94Y and the other is hydrogen or (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy, halo, halo(C1-C6)alkoxy or NRjRk wherein Rj and Rk are independently H, (C1-C6)alkyl or (C1-C6)alkonyl; or R1 and R2 together are oxo (xe2x95x90O);
R3 is hydrogen, halo, carboxy, mercapto, (C1-C6)alkyl, (C3-C8)cycloalkyl, or xe2x80x94Oxe2x80x94Y;
R4 and R5 are each independently hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl;
R6 is hydrogen or is absent when the adjacent xe2x80x94 is a bond;
R7 is hydrogen or (C1-C6)alkyl;
R8 is hydrogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl and R11 is hydrogen, (C1-C6)alkyl carboxy, or hydroxy(C1-C6)alkyl; or R8 and R11 together are xe2x80x94Oxe2x80x94C(xe2x95x90X)xe2x80x94;
R9 and R10, are each independently hydrogen or (C1-C6)alkyl;
each of the bonds represented by xe2x80x94 is independently absent or is present;
X is two hydrogens, oxo (xe2x95x90O) or thioxo (xe2x95x90S);
each Y is independently H, aryl, P(O)(Cl)2, (C3-C8)cycloalkyl, adamantyl, xe2x80x94SO2Ra Oxe2x95x90P(Rb)2, Oxe2x95x90P(Rc)2OP(O)(Rd)xe2x80x94, Si(Re)3, tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and xe2x80x94N(Rf)xe2x80x94; wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (xe2x95x90O), hydroxy, carboxy, halo, mercapto, nitro, xe2x80x94N(Rg)(Rh), (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide; and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
Ra is (C1-C6)alkyl or aryl;
Rb, Rc, and Rd are each independently hydroxy, (C1-C6)alkoxy, hydroxy(C2-C6)alkoxy, adamantyloxy, adamantyl(C1-C6)alkoxy, norbornyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C1-C6)alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C3-C8)cycloalkyloxy, NRxRy, or aryloxy;
Re is H, aryl or (C1-C6)alkyl;
Rf is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl;
Rg and Rh are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, adamantyl, adamantyl(C1-C6)alkyl, amino(C1-C6)alkyl, aminosulfonyl, (C1-C6)alkanoyl, aryl and benzyl; or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical; and
Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, aryl or benzyl;
wherein each aryl of Y, Ra-Rd, Rg-Rh, Rx, and Ry may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NRiRj, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, trifluoromethoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, or (C1-C6)alkanoyloxy; wherein Ri and Rj are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl, or benzyl;
wherein any alkyl can optionally be substituted with one or more polyethyleneimine or poly(ethylene glycol); and wherein any alkyl can optionally be interrupted with one or more polyethyleneimine or poly(ethylene glycol);
or a pharmaceutically acceptable salt thereof.
The invention provides novel compounds of formula (I) and formula (II), as well as intermediates for the synthesis of compounds of formula (I) and formula (II). The invention also provides compounds of formula (I) and (II) that are useful as intermediates for the synthesis of other useful compounds. The invention provides the use of compounds of formula (I) and formula (II) for the manufacture of medicaments useful for the treatment of bacterial infections in a mammal, such as a human. The invention also provides processes for preparing compounds of formula (I) and formula (II).